1. Field of the Invention
This invention provides aryl substituted tetrahydroindazoles, and more specifically to aryl substituted tetrahydroindazoles that bind to the benzodiazepine site of GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of central nervous system (CNS) diseases.
2. Description of the Related Art
The GABAA receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, xcex3-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABAA receptor, which causes alteration in chloride conductance and membrane polarization.
A number of cDNAs for GABAA receptor subunits have been characterized. To date at least 6xcex1, 3xcex2, 3xcex3, 1xcex5, 1xcex4 and 2xcfx81 subunits have been identified. It is generally accepted that native GABAA receptors are typically composed of 2xcex1, 2xcex2, and 1xcex3 subunits (Pritchett and Seeburg Science 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998; 6:1-18). Evidence such as message distribution, genome localization and biochemical study results suggest that the major naturally occurring receptor combinations are xcex11xcex22xcex32, xcex12xcex23xcex32, xcex13xcex23xcex32, and xcex15xcex23xcex32, (Mohler et. al., Neuroch. Res. 1995; 20(5): 631-636).
Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABAA receptor. In addition to the benzodiazepine site, the GABAA receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the barbiturate site. The benzodiazepine site of the GABAA receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for GABA or for other classes of drugs that bind to the receptor (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6th ed., 1991, pp. 145-148, Oxford University Press, New York). Early electrophysiological studies indicated that a major action of the benzodiazepines was enhancement of GABAergic inhibition. Compounds that selectively bind to the benzodiazepine site and enhance the ability of GABA to open GABAA receptor channels are agonists of GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called inverse agonists. Compounds belonging to a third class bind selectively to the benzodiazepine site and yet have little or no effect on GABA activity, but can block the action of GABAA receptor agonists or inverse agonists that act at this site. These compounds are referred to as antagonists.
The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early and the distribution of activities at different receptor subtypes has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have a long history of pharmaceutical use as anxiolytics, these compounds often exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence.
GABAA selective ligands may also act to potentiate the effects of other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when used in combination with GABAA selective ligands than when used alone.
International Application WO 00/40565 discloses tetrahydroindazole derivatives.
This invention provides aryl substituted tetrahydroindazoles, that preferably bind with both high affinity and high selectivity to the benzodiazepine site of the GABAA receptor, including human GABAA receptors.
Thus, the invention provides compounds of Formula I, and pharmaceutical compositions comprising compounds of Formula I.
The invention further comprises methods of treating patients suffering from CNS disorders with an effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pet) or livestock animals suffering from CNS disorders with an effective amount of a compound of the invention is encompassed by the invention.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound.
Additionally this invention relates to the use of the compounds of the invention as probes for the localization of GABAA receptors in tissue sections.
Accordingly, a broad aspect of the invention is directed to compounds of Formula I 
or a pharmaceutically acceptable salt thereof, wherein:
n is 0, 1, or 2;
R1 and R2 are independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, amino, and mono- or dialkylamino;
R3 is hydrogen or C1-6 alkyl;
Ar is aryl or a saturated, unsaturated, or aromatic heterocyclic group, wherein each aryl of heterocyclic group is optionally substituted;
when n is 0 or 2, Ar is optionally substituted with G, when n is 1 Ar is substituted by at least one group G, where
G represents a group of the formula: 
where
W is oxygen, NH, N-alkyl, N-acyl, sulfur, or CR5R6 where R5 and R6 are the same or different and represent hydrogen, alkyl, or R5 and R6 may be taken together to form a saturated or partially unsaturated carbocyclic ring having 3-7 carbon atoms; 
xe2x80x83independently represent straight or branched carbon chains which may be substituted with one, two or three substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mono or dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, haloalkyl, and haloalkoxy;
x is 0, 1, 2, or 3;
y is 0, 1, 2, or 3;
Z is hydrogen, hydroxy, alkoxy, cycloalkyl, cycloalkyl(alkoxy), amino, mono or dialkylamino, or xe2x80x94NR7COR8 where R7 and R8 are the same or different and represent hydrogen or alkyl, or R7 and R8 and the atoms to which they are attached form a heterocycloalkyl ring, or
Z is aryl or a saturated, partially unsaturated, or aromatic heterocyclic group of from 1 to 3 rings, 5 to 8 ring members in each ring and, in at least one of said rings, from 1 to about 3 heteroatoms selected from the group consisting of N, O, and S, wherein each aryl or heterocyclic group optionally substituted.
The invention also provides intermediates and methods of making the compounds of the invention.
Preferred compounds of Formula I are those where R1 and R2 groups include hydrogen, methyl, and ethyl with hydrogen being particularly preferred, R3 is preferably hydrogen or methyl, Ar is preferably phenyl or pyridyl.
Particular compounds of Formula I include compounds wherein:
R1 and R2 are independently chosen at each occurrence from: hydrogen, halogen, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, nitro, cyano, amino, mono- or di(C1-6)alkylamino;
Ar is phenyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, naphthyl, indolyl, quinolinyl, or isoquinolinyl, each of optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, C1-6haloalkoxy, hydroxy, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, halo(C1-3)alkyl, halo(C2-3)alkenyl, halo(C2-3)alkynyl, C1-6 alkoxy, mono or di(C1-6)alkylamino, and G, with the proviso that when n is 1 Ar is substituted by at least one group G;
G is a group of the formula: 
where
W is oxygen, NH, N-acyl, N-alkyl, sulfur, or CR5R6 where R5 and R6 are the same or different and represent hydrogen, straight or branched chain C1-6 alkyl, or R5 and R6 may be taken together to represent a cyclic moiety having 3-7 carbon atoms;
Z is hydrogen, hydroxy, alkoxy, cycloalkyl, cycloalkyl(alkoxy), amino, mono or dialkylamino, or xe2x80x94NR7COR8 where R7 and R8 are the same or different and represent hydrogen or alkyl, or
Z is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, amino, cyano, nitro, hydroxy, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, C1-3haloalkoxy, halo(C1-3)alkyl, halo(C2-3)alkenyl, halo(C2-3)alkynyl, C1-6alkoxy, and mono or di(C1-6)alkylamino; and 
xe2x80x83independently represent straight or branched carbon chains which may be substituted with one, two or three substituents independently selected from the group consisting of hydroxy, halogen, cyano, nitro, amino, mono or di(C1-6)alkylamino, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy;
x is 0, 1, 2, or 3; and
y is 0, 1, 2, or 3.
Such compounds are referred to hereinafter as compounds of Formula II.
Preferred R1 and R2 groups for compounds of Formula II include hydrogen, methyl, and ethyl with hydrogen being particularly preferred. In compounds of Formula II R3 is preferably hydrogen or methyl, and Ar is preferably phenyl, pyrimidinyl, pyridizinyl, pyridyl, or pyrazolyl, more preferably Ar is phenyl, pyridyl, or pyridizinyl.
Other particular compounds embraced within the invention include those of general formula I where
n is 0, 1, or 2;
R1 and R2 are independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, amino, mono- or dialkylamino;
R3 is hydrogen or C1-6 alkyl;
Ar is aryl or a saturated, unsaturated, or aromatic heterocyclic group, wherein each aryl of heterocyclic group is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, hydroxy, nitro, azido, alkanoyl, amino, mono or dialkylamino, haloalkoxy, carboxamido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, aminoalkyl, aryl, arylalkyl, arylalkoxy, heteroaryl heterocycloalkyl;
when n is 0 or 2, Ar is optionally substituted with G where
G represents a group of the formula: 
xe2x80x83where
W is oxygen, NH, N-alkyl, N-acyl, sulfur, or CR5R6 where R5 and R6 are the same or different and represent hydrogen, alkyl, or R5 and R6 may be taken together to form a saturated or partially unsaturated carbocyclic ring having 3-7 carbon atoms; 
xe2x80x83independently represent straight or branched carbon chains which may be substituted with one, two or three substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mono or dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, haloalkyl, and haloalkoxy;
x is 0, 1, 2, or 3; and
y is 0, 1, 2, or 3; and
Z is hydrogen, hydroxy, alkoxy, cycloalkyl, cycloalkyl (alkoxy), amino, mono or dialkylamino, or xe2x80x94NR7COR8 where R7 and R8 are the same or different and represent hydrogen or alkyl, or
R7 and R8 and the atoms to which they are attached form a heterocycloalkyl ring, or
Z is aryl or a saturated, partially unsaturated, or aromatic heterocyclic group of from 1 to 3 rings, 5 to 8 ring members in each ring and, in at least one of said rings, from 1 to about 3 heteroatoms selected from the group consisting of N, O, and S, wherein each aryl or heterocyclic group optionally substituted on each ring with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, hydroxy, nitro, azido, alkanoyl, carboxamido, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, aminoalkyl, aryl, haloalkoxy, amino, mono or dialkylamino, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, arylalkyl, arylalkoxy, heteroaryl, and heterocycloalkyl; or
when n is 1, Ar is substituted with at least one group G where G represents 
xe2x80x83wherein
(i)W is sulfur, and 
xe2x80x83and Z are as defined above;
(ii)W is oxygen, NR10 where R10 is hydrogen, alkyl, or acyl, or W is CR5R6 where R5 and R6 are the same or different and represent hydrogen, alkyl, wherein: 
xe2x80x83and independently represent straight or branched carbon chains which may be substituted with one, two or three substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mono or dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, haloalkyl, and haloalkoxy;
x is 0, 1, 2, or 3; and
y is 1, 2, or 3; and
Z is hydroxy, alkoxy, cycloalkyl, cycloalkyl(alkoxy), amino, mono or dialkylamino, or xe2x80x94NR7COR8 where
R7 and R8 are the same or different and represent hydrogen or alkyl, or
R7 and R8 and the atoms to which they are attached form a heterocycloalkyl ring, or
Z is aryl or a saturated, partially unsaturated, or aromatic heterocyclic group of from 1 to 3 rings, 5 to 8 ring members in each ring and, in at least one of said rings, from 1 to about 3 heteroatoms selected from the group consisting of N, O, and S, wherein each aryl or heterocyclic group optionally substituted on each ring with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, hydroxy, nitro, azido, alkanoyl, carboxamido, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, aminoalkyl, aryl, haloalkoxy, amino, mono or dialkylamino, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, arylalkyl, arylalkoxy, heteroaryl, and heterocycloalkyl;
(iii) W is CR5R6 where R5 and R6 are taken together to form a saturated or partially unsaturated carbocyclic ring, wherein 
xe2x80x83independently represent straight or branched carbon chains which may be substituted with one, two or three substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mono or dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, haloalkyl, and haloalkoxy;
x is 1, 2, or 3; and
y is 0, 1, 2, or 3; and
Z is hydrogen, hydroxy, alkoxy, cycloalkyl, cycloalkyl (alkoxy), amino, mono or dialkylamino, or xe2x80x94NR7COR8 where R7 and R8 are the same or different and represent hydrogen or alkyl, or
R7 and R8 and the atoms to which they are attached form a heterocycloalkyl ring, or
Z is aryl or a saturated, partially unsaturated, or aromatic heterocyclic group of from 1 to 3 rings, 5 to 8 ring members in each ring and, in at least one of said rings, from 1 to about 3 heteroatoms selected from the group consisting of N, O, and S, wherein each aryl or heterocyclic group optionally substituted on each ring with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, hydroxy, nitro, azido, alkanoyl, carboxamido, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, aminoalkyl, aryl, haloalkoxy, amino, mono or dialkylamino, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, arylalkyl, arylalkoxy, heteroaryl, and heterocycloalkyl.
This group of compounds is hereinafter referred to as compounds of Formula III.
Preferred compounds of Formula III include those wherein n is 1;
Ar is phenyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, naphthyl, indolyl, quinolinyl, or isoquinolinyl, each of which is substituted with at least one group G and optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, C1-6haloalkoxy, hydroxy, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl (C1-3)alkyl, halo(C1-3)alkyl, halo(C2-3)alkenyl, halo(C2-3)alkynyl, C1-6 alkoxy, and mono or di(C1-6)alkylamino;
wherein G represents 
xe2x80x83where
Z is hydrogen, hydroxy, alkoxy, cycloalkyl, cycloalkyl(alkoxy), amino, mono or dialkylamino, or xe2x80x94NR7COR8 where R7 and R8 are the same or different and represent hydrogen or alkyl, or
Z is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, amino, cyano, nitro, hydroxy, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, C1-3haloalkoxy,halo(C1-3)alkyl, halo(C2-3)alkenyl, halo(C2-3)alkynyl, C1-6alkoxy, and mono or di(C1-6)alkylamino; and 
xe2x80x83independently represent straight or branched carbon chains which may be substituted with one, two or three substituents independently selected from the group consisting of hydroxy, halogen, cyano, nitro, amino, mono or di(C1-6)alkylamino, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy;
x is 0, 1, 2, or 3; and
y is 0, 1, 2, or 3
(hereinafter compounds of Formula III-A)
Preferred compounds of Formula III-A include those where
Ar is phenyl, pyridyl, pyrimidinyl, pyridizinyl or pyrazolyl, each of which is substituted with at least one group G and optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, hydroxy, amino, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C3-7cycloalkyl, C3-7cycloalkyl (C1-3) alkyl, halo(C1-3)alkyl, halo (C1-3) alkoxy, halo (C2-3) alkenyl, halo (C2-3) alkynyl, C1-6 alkoxy, and mono or di(C1-6)alkylamino;
Z is hydrogen, hydroxy, C1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkyl(C1-3alkoxy), amino, mono or di(C1-6)alkylamino, or xe2x80x94NR7COR8 where R7 and R8 are the same or different and represent hydrogen or C1-6alkyl, or
Z is morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, amino, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, halo(C1-3)alkyl, halo (C1-3)alkoxy, C1-6 alkoxy, or mono and di(C1-6)alkylamino; and 
xe2x80x83independently represent methylene groups; where
x is 0, 1, 2, or 3; and
y is 0, 1, 2, or 3.
Other preferred compounds of Formula III-A are those where x is 0.
Yet other preferred compounds of Formula III-A are those where
Z is hydrogen, hydroxy, C1-6 alkoxy, C3-7cycloalkyl(C1-3alkoxy), amino, or mono or di(C1-6)alkylamino, or
Z is morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally mono-, di-, or trisubstituted independently with substituents independently chosen from halogen, amino, cyano, nitro, C1-6haloalkyl, C1-6haloalkyoxy, hydroxy, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkyl(C1-3)alkyl, halo(C1-3)alkyl, halo (C1-3) alkoxy, C1-6 alkoxy, and mono or di(C1-6)alkylamino.
Still more preferred compounds of Formula III-A are those where
Z is amino, mono or di(C1-6)alkylamino, or
Z is morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally mono- or disubstituted with substituents independently chosen from halogen, amino, cyano, nitro, C1-2haloalkyl, C1-2haloalkoxy, hydroxy, C1-6 alkyl, C1-6 alkoxy, and mono or di(C1-6)alkylamino.
More preferred compounds of Formula III include those where
n is 1;
Ar is phenyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, quinolinyl, isoquinolinyl, pyrazolyl, or pyridizinyl, each of which is substituted with at least one group G and optionally mono-, di-, or trisubstituted with halogen, cyano, nitro, hydroxy, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, halo(C1-3)alkyl, halo(C1-3)alkoxy, halo(C2-3)alkenyl, halo(C2-3)alkynyl, C1-6 alkoxy, or mono or di(C1-6)alkylamino;
wherein G represents 
xe2x80x83where 
xe2x80x83independently represent straight or branched carbon chains which may be substituted with one, two or three substituents independently selected from the group consisting of hydroxy, halogen, cyano, nitro, amino, mono or di(C1-6)alkylamino, C1-6alkyl C2-6alkenyl, C3-7cycloalkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy;
x is 0, 1, or 2;
y is 1, 2, or 3; and
Z is hydroxy, C1-6alkoxy, C3-7cycloalkyl (C13alkoxy), amino, mono or di(C1-6)alkylamino, or xe2x80x94NR7COR8 where R7 and R8 are the same or different and represent hydrogen or C1-6alkyl, or
Z is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, morpholinyl, pyrrolidinyl, piperidinyl, pyridizinyl, or piperazinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, amino, cyano, nitro, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, halo(C1-3)alkyl, halo(C1-3)alkoxy, halo(C2-3)alkenyl, halo(C2-3)alkynyl, C1-6 alkoxy, and mono or di(C1-6)alkylamino
(hereinafter referred to as compounds of Formula III-B).
Preferred compounds of Formula III-B include those where
Ar is phenyl, pyridyl, pyrimidinyl, pyridizinyl or pyrazolyl, each of which is substituted with at least one group G and optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, hydroxy, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, halo(C1-3)alkoxy, halo(C1-3)alkyl, halo(C2-3)alkenyl, halo(C2-3)alkynyl, C1-6 alkoxy, and mono or di(C1-6)alkylamino;
Z is hydroxy, alkoxy, cycloalkyl(alkoxy), amino, mono- or di(C1-C6)alkylamino, or xe2x80x94NR7COR8 where R7 and R8 are the same or different and represent hydrogen or C1-C6 alkyl, or
Z is morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, halo(C1-3)alkyl, C1-6 alkoxy, and mono or di(C1-6)alkylamino; and 
xe2x80x83independently represent methylene groups; where
x is 0, 1, 2, or 3; and
y is 1, 2, or 3.
More preferred compounds of Formula III-B are those wherein x is 0.
Still other more preferred compounds of Formula III-B are those where
Z is hydroxy, C1-C6 alkoxy, C3-C7 cycloalkyl(C1-C6)alkoxy, amino, or mono- or di(C1-C6)alkylamino, or
Z is morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, amino, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, halo(C1-3)alkyl, halo(C1-3)alkoxy, C1-6 alkoxy, and mono or di(C1-6)alkylamino.
Further more preferred compounds of Formula III-B are those where y is 1, 2, or 3;
Z is amino, or mono- or di(C1-C4)alkylamino, or
Z is morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally mono- or disubstituted independently with C1-6 alkyl, or mono or di(C1-6)alkylamino.
Particularly preferred compounds of Formula III-B are those where
Z is amino, mono or di(C1-C6)alkylamino, or
Z is morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally mono- or disubstituted independently with C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, or C1-6 alkyl.
Other particularly preferred compounds of Formula III-B are those where Z is mono or di(C1-C3)alkylamino.
Still other particularly preferred compounds of Formula III-B are those where y is 1, 2, or 3 and Z is C1-C3 alkylamino.
Yet other particularly preferred compounds of Formula III-B are those where R1 and R2 are independently selected from hydrogen, halogen, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-2haloalkyl, C1-2haloalkoxy, nitro, cyano, amino, and mono- and di(C1-6)alkylamino.
Other particularly preferred compounds of Formula III-B are those where R1 and R2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-2 alkyl, C1-2alkoxy, C1-2haloalkyl, and C1-2haloalkoxy.
Other more preferred compounds of Formula III include those where
n is 1;
Ar is phenyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, quinolinyl, pyrazolyl, pyridizinyl, or isoquinolinyl, each of which is substituted with at least one group G and optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, hydroxy, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7cycloalkyl(C1-3)alkyl, halo(C1-3)alkyl, halo(C1-3)alkoxy, halo(C2-3)alkenyl, halo(C2-3)alkynyl, C1-6 alkoxy, and mono or di(C1-6)alkylamino;
wherein G represents 
xe2x80x83where R10 is hydrogen, C1-6 alkyl, or C2-6 acyl; 
xe2x80x83independently represent straight or branched carbon chains which may be substituted with one, two or three substituents independently selected from the group consisting of hydroxy, halogen, cyano, nitro, amino, mono or di(C1-6)alkylamino, C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy;
x is 0, 1, or 2;
y is 1, 2, or 3; and
Z is hydroxy, alkoxy, C3-7cycloalkyl (C1-3alkoxy), amino, mono or di(C1-6)alkylamino, or xe2x80x94NR7COR8 where R7 and R8 are the same or different and represent hydrogen or C1-6alkyl, or
Z is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, morpholinyl, pyrrolidinyl, piperidinyl, pyridizinyl, or piperazinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, amino, cyano, nitro, hydroxy, C1-6 alkyl, C2-6alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, halo(C1-3)alkyl, halo(C1-3)alkoxy, halo(C2-3)alkenyl, halo(C2-3)alkynyl, C1-6 alkoxy, and mono or di(C1-6)alkylamino.
(hereinafter referred to as compounds of Formula III-C).
Preferred compounds of Formula III-C are those wherein:
R10 is hydrogen or C1-C6 alkyl;
Ar is phenyl, pyridyl, pyrimidinyl, pyridizinyl or pyrazolyl, each of which is substituted with at least one group G and optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, hydroxy, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, halo(C1-3)alkoxy, halo(C1-3)alkyl, halo (C2-3) alkenyl, halo(C2-3)alkynyl, C1-6 alkoxy, and mono or di(C1-6)alkylamino;
Z is hydroxy, alkoxy, cycloalkyl(alkoxy), amino, mono- or di(C1-C6)alkylamino, or xe2x80x94NR7COR8 where R7 and R8 are the same or different and represent hydrogen or C1-C6 alkyl, or
Z is morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, halo(C1-3)alkyl, C1-6 alkoxy, and mono or di(C1-6)alkylamino; and 
xe2x80x83independently represent methylene groups; where
x is 0, 1, 2, or 3; and
y is 1, 2, or 3.
More preferred compounds of Formula III-C are those wherein x is 0 and R10 is hydrogen or methyl.
Still other more preferred compounds of Formula III-C are those where
Z is hydroxy, C1-C6 alkoxy, C3-C7 cycloalkyl(C1-C6)alkoxy, amino, or mono- or di(C1-C6)alkylamino, or
Z is morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, amino, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, halo (C1-3)alkyl, halo (C1-3)alkoxy, C1-6 alkoxy, and mono or di(C1-6)alkylamino.
Further more preferred compounds of Formula III-C are those where
y is 1, 2, or 3;
Z is amino, or mono- or di(C1-C4)alkylamino, or
Z is morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally mono- or disubstituted independently with C1-6 alkyl, or mono or di(C1-6)alkylamino.
Particularly preferred compounds of Formula III-C are those where
Z is amino, mono or di(C1-C6)alkylamino, or
Z is morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally mono- or disubstituted independently with C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, or C1-6 alkyl.
Other particularly preferred compounds of Formula III-C are those where Z is mono or di(C1-C3)alkylamino.
Still other particularly preferred compounds of Formula III-C are those where y is 1, 2, or 3 and Z is C1-C2 alkylamino.
Yet other particularly preferred compounds of Formula III-C are those where R1 and R2 are independently selected from hydrogen, halogen, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-2haloalkyl, C1-2haloalkoxy, nitro, cyano, amino, and mono- and di(C1-6)alkylamino.
Other particularly preferred compounds of Formula III-C are those where R1 and R2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-2 alkyl, C1-2 alkoxy, C1-2haloalkyl, and C1-2haloalkoxy.
Preferred compounds of Formulae I, II and III are those where R3 is hydrogen.
Another particular group of compounds is those of Formula IV, i.e., compounds of general formula I where
n is 0 or 2;
R1 and R2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-2 alkyl, C1-2 alkoxy, C1-2haloalkyl, and C1-2haloalkoxy;
Ar is phenyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, naphthyl, indolyl, quinolinyl, or isoquinolinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, C1-6haloalkyl, C1-6haloalkoxy, hydroxy, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, halo(C1-3)alkyl, halo(C2-3)alkenyl, halo(C2-3)alkynyl, C1-6 alkoxy, mono or di(C1-6)alkylamino and G; wherein
G represents 
xe2x80x83where
W is nitrogen, oxygen, or CR5R6 where R5 and R6 are the same or different and represent hydrogen or straight or branched chain C1-6 alkyl;
Z is selected from the group consisting of hydrogen, hydroxy, C1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkyl (C1-3alkoxy) amino, and mono or di(C1-6)alkylamino; or
Z is piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyridizinyl, each of which is optionally substituted with one, two, or three groups independently selected from the group consisting of halo(C1-C6)alkyl, halo(C1-C6)alkoxy, halogen, C1-6 alkyl, hydroxy, and C1-6 alkoxy; 
xe2x80x83represent straight or branched carbon chains which may be substituted with one, two or three substituents independently selected from the group consisting of hydroxy, halogen, amino, mono or di(C1-6)alkylamino, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy;
x is 0, 1, 2, or 3; and
y is 0, 1, 2, or 3.
Preferred compounds of Formula IV are those where Ar is phenyl, pyrazolyl, pyridyl, pyrimidinyl, or pyridizinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, C1-6haloalkyl, C1-6haloalkoxy, hydroxy, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-3)alkyl, halo(C1-3)alkyl, halo(C2-3)alkenyl, halo(C2-3)alkynyl, C1-6 alkoxy, mono or di(C1-6)alkylamino and G.
More preferred compounds of Formula IV are those where Ar is phenyl, pyrazolyl, pyridyl, pyrimidinyl, or pyridizinyl, each of which is substituted with at least one G and optionally substituted with one or two groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, amino, and mono- and di(C1-C6)alkylamino.
Preferred compounds of Formulae III-B and III-C include those where R1 and R2 are independently selected at each occurrence from hydrogen, methyl and ethyl.
Particularly preferred compounds of Formulae III-B and III-C are those where no more than three of R1 and R2 are other than hydrogen.
Other particularly preferred compounds of Formulae III-B and III-C include those where one, two, or three of R1 and R2 is methyl or ethyl, and the remaining R1 and R2 substituents are hydrogen.
Particularly preferred compounds of Formulae III-A are those where one, two, or three of R1 and R2 is methyl or ethyl, and the remaining R1 and R2 substituents are hydrogen.
Other particularly preferred compounds of Formula III-A are those where Ar is phenyl, pyridizinyl, or pyridyl, each of which is
a) substituted with one group selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, amino, and mono- and di(C1-C2)alkylamino; and
b) substituted with C1-C3 alkoxy substituted with: C1-C3 alkylamino, di (C1-C3) alkylamino, amino, morpholino, piperazinyl, 4-(C1-4) alkylpiperazinyl, piperidinyl or piperidinyl optionally substituted with C1-C4 alkyl.
Particularly preferred compounds of Formula III-B and Formula III-C are those where phenyl, pyridyl, or pyridizinyl, each of which is
(a) substituted with one group selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, amino, and mono- and di(C1-C2)alkylamino; and
(b) substituted with C1-C3 alkoxy substituted with: C1-C3 alkylamino, di (C1-C3) alkylamino, amino, morpholino, piperazinyl, 4-(C1-4) alkylpiperazinyl, piperidinyl or piperidinyl optionally substituted with C1-C4 alkyl.
This invention provides aryl substituted tetrahydroindazoles. Preferred examples of the invention bind with high affinity to the benzodiazepine site of GABAA receptors, including human GABAA receptors. Particularly preferred compounds are those that bind with high selectivity to the benzodiazepine site of GABAA receptors, including human GABAA receptors. Without wishing to be bound to any particular theory, it is believed that the interaction of the compounds of Formula I with the benzodiazepine site results in the pharmaceutical utility of these compounds.
The invention further comprises methods of treating patients in need of such treatment with an amount of a compound of the invention sufficient to alter the symptoms of a CNS disorder. Compounds of the invention that act as agonists at xcex12xcex23xcex32 and xcex13xcex23xcex32 receptor subtypes are useful in treating anxiety disorders such as panic disorder, obsessive compulsive disorder and generalized anxiety disorder; stress disorders including post-traumatic stress, and acute stress disorders. Compounds of the invention that act as agonists at xcex12xcex23xcex32 and xcex13xcex23xcex32 receptor subtypes are also useful in treating depressive or bipolar disorders and in treating sleep disorders. Compounds of the invention that act as inverse agonists at the xcex15xcex23xcex32 receptor subtype or xcex11xcex22xcex32 and xcex15xcex23xcex32 receptor subtypes are useful in treating cognitive disorders including those resulting from Down Syndrome, neurodegenerative diseases such as Alzheimer""s disease and Parkinson""s disease, and stroke related dementia. Compounds of the invention that act as agonists at the xcex11xcex22xcex32 receptor subtype are useful in treating convulsive disorders such as epilepsy. Compounds that act as antagonists at the benzodiazepine site are useful in reversing the effect of benzodiazepine overdose and in treating drug and alcohol addiction.
The diseases and/or disorders that can also be treated using compounds and compositions according to the invention include:
Depression, e.g. depression, atypical depression, bipolar disorder, depressed phase of bipolar disorder.
Anxiety, e.g. general anxiety disorder (GAD), agoraphobia, panic disorder+/xe2x88x92agoraphobia, social phobia, specific phobia, Post traumatic stress disorder, obsessive compulsive disorder (OCD), dysthymia, adjustment disorders with disturbance of mood and anxiety, separation anxiety disorder, anticipatory anxiety acute stress disorder, adjustment disorders, cyclothymia.
Sleep disorders, e.g. sleep disorders including primary insomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, including nightmare disorder, sleep terror disorder, sleep disorders secondary to depression and/or anxiety or other mental disorders, substance induced sleep disorder.
Cognition Impairment, e.g. cognition impairment, Alzheimer""s disease, Parkinson""s disease, mild cognitive impairment (MCI), age-related cognitive decline (ARCD), stroke, traumatic brain injury, AIDS associated dementia, and dementia associated with depression, anxiety or psychosis.
Attention Deficit Disorder, e.g. attention deficit disorder (ADD), and attention deficit and hyperactivity disorder (ADHD).
The invention also provides pharmaceutical compositions comprising compounds of the invention, including packaged pharmaceutical compositions for treating disorders responsive to GABAA receptor modulation, e.g., treatment of anxiety, depression, sleep disorders or cognitive impairment by GABAA receptor modulation. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one GABAA receptor modulator as described supra and instructions (e.g., labeling) indicating the contained GABAA receptor ligand is to be used for treating a disorder responsive to GABAA receptor modulation in the patient.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds, which comprises administering an effective amount of a compound of the invention in combination with another CNS active compound. Such CNS active compounds include, but are not limited to the following: for anxiety, serotonin receptor (e.g. 5-HT1A) agonists and antagonists; for anxiety and depression, neurokinin receptor antagonists or corticotropin releasing factor receptor (CRF1) antagonists; for sleep disorders, melatonin receptor agonists; and for neurodegenerative disorders, such as Alzheimer""s dementia, nicotinic agonists, muscarinic agents, acetylcholinesterase inhibitors and dopamine receptor agonists. Particularly the invention provides a method of potentiating the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) by administering an effective amount of a GABA agonist compound of the invention in combination with an SSRI.
Combination administration can be carried out in a fashion analogous to that disclosed in Da-Rocha, et al., J. Psychopharmacology (1997) 11(3) 211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; or Le, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132. Also see, the discussion of the use of the GABAA receptor ligand 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a]phthalazine in combination with nicotinic agonists, muscarinic agonists, and acetylcholinesterase inhibitors, in PCT International publications Nos. WO 99/47142, WO 99/47171, and WO 99/47131, respectively. Also see in this regard PCT International publication No. WO 99/37303 for its discussion of the use of a class of GABAA receptor ligands, 1,2,4-triazolo[4,3-b]pyridazines, in combination with SSRIs.
The invention also pertains to methods of inhibiting the binding of benzodiazepine compounds, such as Ro15-1788, to the GABAA receptors which methods involve contacting a compound of the invention with cells expressing GABAA receptors, wherein the compound is present at a concentration sufficient to inhibit benzodiazepine binding to GABAA receptors in vitro. This method includes inhibiting the binding of benzodiazepine compounds to GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to inhibit the binding of benzodiazepine compounds to GABAA receptors in vitro. In one embodiment, such methods are useful in treating benzodiazepine drug overdose. The amount of a compound that would be sufficient to inhibit the binding of a benzodiazepine compound to the GABAA receptor may be readily determined via an GABAA receptor binding assay, such as the assay described in Example 8. The GABAA receptors used to determine in vitro binding may be obtained from a variety of sources, for example from preparations of rat cortex or from cells expressing cloned human GABAA receptors.
The invention also pertains to methods for altering the signal-transducing activity, particularly the chloride ion conductance of GABAA receptors, said method comprising exposing cells expressing such receptors to an effective amount of a compound of the invention. This method includes altering the signal-transducing activity of GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to alter the signal-transducing activity of GABAA receptors in vitro. The amount of a compound that would be sufficient to alter the signal-transducing activity of GABAAxe2x80x94receptors may be determined via a GABAA receptor signal transduction assay, such as the assay described in Example 9.
The GABAA receptor ligands provided by this invention and labeled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the GABAA receptor.
Labeled derivatives of the GABAA receptor ligands provided by this invention are also useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
The compounds herein described may have one or more asymmetric centers. Compounds of the invention containing an asymmetrically substituted atom may be isolated in enantiomerically enhanced or racemic form. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms (racemates), by asymmetric synthesis, or by synthesis from optically active starting materials. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; derivatizing with an enantiomerically enriched resolving reagent, separating the resulting diastereomers through means well known in the art, and removing the enantiomerically enriched derivatizing agent through ordinary chemical means such as, for example, hydrolysis or hydrogenation; or chromatography, using, for example a chiral HPLC column.
Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the invention. Cis, trans Z and E geometric isomers of the compounds of the invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral (enantiomeric and diastereomeric), and racemic forms, as well as all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
Some compounds of the invention may exist as tautomers. Unless otherwise specified, any description or claim of one tautomeric form is intended to encompass the other tautomer.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valence is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. The invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 11C, 13C, and 14C.
When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R*, then said group may optionally be substituted with up to two R* groups and each R* is selected independently from the definition of R*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
Where the term xe2x80x9calkylxe2x80x9d is used, either alone or within other terms such as xe2x80x9chaloalkylxe2x80x9d and xe2x80x9calkylsulfonylxe2x80x9d, it embraces linear, i.e., straight, and branched chain groups having one to about twelve carbon atoms. Preferred alkyl groups are xe2x80x9clower alkylxe2x80x9d groups having one to about ten carbon atoms. More preferred are lower alkyl groups having one to about six carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and sec-pentyl and the like. Preferred alkyl groups are C1-C6 alkyl groups. Especially preferred alkyl groups are methyl, ethyl, propyl, butyl, 3-pentyl. The term C1-C6 alkyl as used herein includes alkyl groups having from 1 to 6 carbon atoms. Preferred examples are methyl and ethyl.
xe2x80x9cAlkylsulfonylxe2x80x9d embraces alkyl groups attached to a sulfonyl group, where alkyl is defined as above, i.e., a group of the formula xe2x80x94SOa(alkyl). More preferred alkylsulfonyl groups are xe2x80x9clower alkylsulfonylxe2x80x9d groups having one to six carbon atoms. Examples of such lower alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
The term xe2x80x9calkylsulfinylxe2x80x9d embraces groups containing a linear or branched alkyl group, of one to ten carbon atoms, attached to a divalent xe2x80x94S(xe2x95x90O)xe2x80x94 atom.
The terms xe2x80x9cN-alkylaminoxe2x80x9d and xe2x80x9cN,N-dialkylaminoxe2x80x9d denote amino groups which have been substituted with one alkyl group and with two alkyl groups, respectively. More preferred alkylamino groups are xe2x80x9clower alkylaminoxe2x80x9d groups having one or two alkyl groups of one to six carbon atoms, attached to a nitrogen atom. Suitable xe2x80x9calkylaminoxe2x80x9d may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.
The term xe2x80x9calkylthioxe2x80x9d embraces groups containing a linear or branched alkyl group, of one to ten carbon atoms, attached to a divalent sulfur atom. An example of xe2x80x9calkylthioxe2x80x9d is methylthio, (CH3xe2x80x94Sxe2x80x94).
The term xe2x80x9ccycloalkylxe2x80x9d embraces groups having three to ten carbon atoms. More preferred cycloalkyl groups are xe2x80x9clower cycloalkylxe2x80x9d groups having three to seven carbon atoms, i.e., C3-c7 cycloalkyl. Examples include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
In the term xe2x80x9cC3-C7 cycloalkylalkylxe2x80x9d, the C3-7 cycloalkyl group is attached to the parent molecular moiety through the alkyl, preferably a C1-C6, more preferably a C1-C4 alkyl, group. This term encompasses, but is not limited to, cyclopropylmethyl, and cyclohexylmethyl.
By xe2x80x9ccarboxamidoxe2x80x9d as used herein is meant groups of the formula xe2x80x94C(O)NRxe2x80x2Rxe2x80x3 where Rxe2x80x2 and Rxe2x80x3 are the same or different and represent hydrogen or alkyl. Preferred carboxamido groups are those where both of Rxe2x80x2 and Rxe2x80x3 are hydrogen.
The term xe2x80x9calkenylxe2x80x9d embraces unsaturated straight and branched chain groups having two to about ten carbon atoms. Such groups contain at least one carbon-carbon double bond which may occur at any stable point along the chain. Examples of alkenyl groups include, but are not limited to such groups as ethenyl and propenyl.
The term xe2x80x9calkynylxe2x80x9d embraces straight and branched chain groups having two to about ten carbon atoms and at least one carbon-carbon triple bond. The carbon-carbon triple bond may occur at any stable point along the chain. Examples of alkynyl groups include, but are not limited to such groups as ethynyl and propynyl.
xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. More preferred alkoxy groups include methoxy, ethoxy, isopropoxy, and isobutoxy.
As used herein, xe2x80x9calkanoylxe2x80x9d and xe2x80x9cacylxe2x80x9d refer to an alkyl group as defined above attached through a carbonyl bridge, i.e., xe2x80x94CO(alkyl). Examples include acetyl, propionyl, and butyryl.
The term xe2x80x9carylxe2x80x9d is used to indicate aromatic groups that contain only carbon atoms in the ring structure. Thus, the term xe2x80x9carylxe2x80x9d refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups are, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, indanyl, and biphenyl. Preferred aryl groups include phenyl, naphthyl, including 1-naphthyl and 2-naphthyl, and acenaphthyl. More preferred aryl groups include phenyl and napthyl. The aryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. Thus, such aryl groups are optionally substituted with, for example, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl.
The term xe2x80x9chaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CVFW where v=1 to 3 and W=1 to (2v+1). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. Preferred haloalkyl groups are halo(C1-C6)alkyl groups; particularly preferred are trifluoromethyl, perfluoropropyl, and difluoromethyl.
By xe2x80x9chaloalkoxyxe2x80x9d as used herein is meant represents a haloalkyl group, as defined above, attached through an oxygen bridge to a parent group. Preferred haloalkoxy groups are halo(C1-C6)alkoxy groups. Examples of haloalkoxy groups are trifluoromethoxy, 2,2-difluoroethoxy, 2,2,3-trifluoropropoxy and perfluoroisopropoxy. The term xe2x80x9chalogenxe2x80x9d indicates fluorine, chlorine, bromine, and iodine.
As used herein, the term xe2x80x9cheterocycloalkylxe2x80x9d is intended to mean a stable 5-to 7-membered monocyclic or 7-to 10-membered bicyclic ring system which contains at least one non-aromatic ring wherein said ring consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. The heterocycloalkyl ring or heterocycloalkyl bicyclic ring system may be fused to a benzene ring. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycloalkyl group exceeds 1, then these heteroatoms are not adjacent to one another. It is also preferred that the total number of S and O atoms in the heterocycloalkyl is not more than 1. Examples of heterocycloalkyl groups include but are not limited to tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrrolyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, azetidinyl, 2H-pyrrolyl.
Non-toxic pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or salts of organic acids such as formic, citric, malic, maleic, fumaric, tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. The invention also encompasses prodrugs of the compounds of Formula I.
The invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies, which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I. Those skilled in the art will also recognize a wide variety of non-toxic pharmaceutically acceptable solvents that may be used to prepare solvates of the compounds of the invention, such as water, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide.
The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred. The term parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It may be convenient to formulate these animal feed and drinking water compositions so that the animal ingests an appropriate quantity of the composition during a meal or throughout the course of the day. It may also be convenient to present the composition as a premix for addition to the feed or drinking water.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of anxiety, depression, or cognitive impairment a dosage regimen of 1 or 2 times daily is particularly preferred. For the treatment of sleep disorders a single dose that rapidly reaches effective concentrations is desirable.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Preferred compounds of the invention have desirable pharmacological properties that include, but are not limited to, oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lives. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat peripheral disorders are often preferred.
Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocytes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.
Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcovxc3xa1, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27).
Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).